Cefprozil, as disclosed in U.S. Pat. No. 4,520,022, is a commercially valuable and therapeutically useful semi-synthetic, broad-spectrum oral cephalosporin antibiotic effective in controlling diseases caused by a wide variety of Gram positive and Gram negative microorganisms.
Because of its therapeutic usefulness and broad, efficient spectrum of activity, there is always a need for an improved synthetic process which would result in a product with high purity and yield, with minimum level of impurities, preferably absent, coupled with ease of operation and, more importantly, with low production cost.
In methods disclosed in prior art, synthesis of Cefprozil has essentially been carried out by amidification of a 7-amino-3-(1-propen-1-yl)-cephem derivative with α-amino-p-hydroxyphenylacetic acid or its reactive derivative as disclosed in the following patents.
U.S. Pat. Nos. 4,520,022 and 4,699,979 (Hoshi et al.) disclose a synthetic process for preparation of Cefprozil by condensation of benzhydryl-7-amino-3-halomethyl-3-cephem-4-carboxylate with D-2-(t-butoxycarbonylamino)-2-(p-hydroxyphenyl)acetic acid in the presence of N,N′-dicyclohexylcarbodiimide (DCC) as the coupling agent and subsequent fuctionalization of the 3α position by Wittig reaction. The chemistry is summarized hereinbelow in Scheme I.

One of the limitations of the process is that it employs DCC which is toxic, expensive and requires rigorous anhydrous conditions. Also dicylohexylurea is formed as a byproduct during the process, removal of which calls for several tedious chromatographic purification and isolation steps to be employed to get the product in pure form.
U.S. Pat. Nos. 3,970,651, 3,985,747 and GB 1,532,682 disclose methods for preparation of Cefprozil, Cefadroxil and Cefatrizine which generally comprise reaction of 4-hydroxyphenylglycine with phosgene, followed by addition of gaseous hydrogen chloride to give 4-hydroxyphenylglycine chloride hydrochloride. This is further reacted with a suitable 7-amino-3-substituted cephem derivative to give the desired cephalosporin antibiotic.
However, these methods employ toxic and hazardous phosgene and gaseous HCl, which are difficult to handle on an industrial scale and cause environmental problem.
PCT application WO 98/04732 discloses a method for preparation of Cefprozil comprising reaction of 4-hydroxyphenylglycine with ethylene glycol to give an ester which is reacted with 7-Amino-3-(propen-1-yl)-3-cephem-4-carboxylic acid (7-APCA), of formula (II), in presence of enzyme, acylase. However, this method utilizes excess amount of the expensive enzyme rendering the method uneconomical.

A salt of 7-APCA with amidine and its use in the production of Cefprozil is disclosed by Greil et al. in the PCT application WO03/011871. The application describes the production of Cefprozil by the reaction of an amidine salt of 7-APCA with a mixed carboxylic acid anhydride of a N-substituted-α-amino-p-hydroxyphenylacetic acid. The patent does not comment on the purity or yield of the product.
All the prior art methods discussed hereinabove are associated with the formation of varying amounts of impurities which affect the overall yield and the quality of the product. Also removal of these impurities calls for additional purification and isolation steps which render the process lengthy and tedious.
Regulatory authorities all over the world are becoming very stringent about the purity of an approved drug. Especially there is growing concern about the nature and level of impurities present in such molecules. US Pharmacopoeia specifies that the purity of Cefprozil should be between 90 to 105%. However, most of the prior art methods are associated with the formation of varying amounts of impurities and hence do not give product conforming to this criterion.
Cephalosporin antibiotics carrying the D-α-amino-α-(4-hydroxyphenyl)acetamido addendum at the 7-position such as Cefprozil and Cefadroxil are generally prepared by reacting the respective 7-amino-3-substituted-3-cephem-4-carboxylic acid or its salt/derivative with an activated derivative of 4-hydroxyphenylglycine such as a reactive ester, a reactive amide or a mixed acid anhydride. However, use of reactive amide or esters makes it difficult to obtain the desired product in high purity and yield because of the occurrence of side-reactions as well as racemization.
Of the activated derivatives of 4-hydroxyphenylglycine, the mixed anhydride of α-amino-p-hydroxyphenylacetic acid of formula III or IIIa:
wherein R1 is an alkyl or an aryl group and R2 is methyl or ethyl,is generally prepared by reacting N-substituted-α-amino-p-hydroxyphenylacetic acid or its salt (Dane salt) with an appropriate acylating agent at an appropriate temperature. For example in the process disclosed in U.S. Pat. No. 3,985,741, the mixed anhydride is prepared by adding the acylating agent, base and the Dane salt to dry acetone at −10° C. and stirring the slurry for 20 minutes. As per the process disclosed in U.S. Pat. No. 4,218,474, the mixed anhydride is prepared by adding a chloroformate, such as ethylchloroformate, to a solution of N-protected-4-hydroxy phenylglycine dissolved in an inert organic solvent at a temperature of −5° to 0° C. in the presence of a base. According to the method disclosed in WO03/011871, the mixed acid anhydride is prepared by adding a base and Dane salt to an inert organic solvent at ambient temperature, cooling the suspension to −30° C., followed by addition of the acylating agent and stirring.
Most of the prior art methods for preparation of the mixed acid anhydride are associated with the formation of varying amounts of different impurities. For example, during the preparation of mixed the 4-hydroxy group of the Dane salt is likely to react with the acylating agent thereby forming an impurity which further reacts with 7-APCA or its salts to form an impurity of formula (IV).

During the course of the present invention, the inventors have reproduced the process for preparation of Cefprozil as disclosed in WO03/011871. It was observed that the preparation of mixed acid anhydride by the method reported in WO03/011871 and its subsequent reaction with amidine salt of 7-APCA is associated with the formation of impurities in the range of 6-7%. Preparation of mixed anhydride as disclosed in U.S. Pat. No. 3,985,741 and its subsequent reaction with 7-aminodesacetoxycephalosporanic acid (7-ADCA) or a salt thereof gives 37% conversion to Cefadroxil of formula (V) with impurities to the tune of 30-35%.

In the prior art methods, cephalosporin antibiotics such as Cefprozil and Cefadroxil have been prepared by reacting the mixed acid anhydride with respective 7-amino-3-substituted-3-cephem-4-carboxylic acid or its salt/derivative such as an amidine salt of 7-APCA as disclosed in WO03/011871 and 7-ADCA or its salt as disclosed in U.S. Pat. No. 3,985,741. However, use of 7-amino-3-substituted-3-cephem-4-carboxylic acid, its acid salt or an amidine salt as disclosed in these prior art methods is found to give the product in low yield due to side reactions of the unprotected 4-carboxylic acid group and 7-amino group.
Hence there is a need to for a protected form of 7-APCA, which will activate the amino group in the 7-position, efficiently protect the carboxylic acid group, which will not require additional deprotection steps and can be deprotected in-situ during reaction work-up.
In summary, the prior art methods for preparation of Cefprozil:    i) utilize toxic and expensive chemicals such as phosgene, DCC and HCl;    ii) utilize expensive enzyme like acylase; and    iii) are associated with formation of varying amounts of impurities which give the product in low purity and yield, rendering such methods less cost effective.
Therefore, a need exists for a simple and cost-effective method for the preparation of Cefprozil in high purity and yield. Such a need could be met through minimization of the impurities associated with the prior art methods with concurrent improvement in the purity and yield of the product.